Investigating the gut-lung axis metabolic profiling and the effect of SCFAs on airway epithelium in healthy and asthmatics

Asthma is a chronic inflammatory disease characterized by decline in lung function, goblet cell metaplasia and tissue remodeling. Recent years have demonstrated the interplay between the airways and the gut microbiota, showcasing the dampening of airway inflammation by gut-microbial metabolites short-chain fatty acids (SCFAs) in rodent models. No studies have investigated the presence and effect of SCFAs in the airways of asthmatics and limited studies have investigated the metabolic profile of asthmatics and the effect of fibre supplementation. We demonstrate the presence of SCFAs (mainly acetate and propionate) in the airways of healthy controls and asthmatics, with an increase in acetate in asthmatics. The levels of SCFAs detected in the airways exceeded what has previously been described in peripheral blood. SCFA concentrations in asthmatic airway were correlated with specific airway microbial genera, suggesting a possible production of SCFAs by the airway microbiota. This was further confirmed by in vitro batch culture, where airway bacterial species produced higher amount of SCFAs in the presence of mucin, indicating proteolytic activity by the airway microbiota. In order to determine the direct effect, which local SCFA level could have on the airway epithelium, the effect of acetate and propionate were investigated on primary airway epithelium. Both SCFAs promoted a modulation of cytokine gene response upon, stimulation on both apical and basolateral side, which was further enhanced by IL-13 treatment. These results suggest that the microbial-airway-derived SCFAs promote a local change in the inflammatory response in vitro, which is different to the response seen with gut-microbial-derived SCFAs in preclinical data. Furthermore, the metabolic profile of asthmatics was investigate using 1H NMR spectroscopy and UPLC-MS, in order to identify potential urinary biomarkers that would aid in the diagnosis of asthma and sub-populations of asthma. Several urinary biomarkers were found to be either elevated or decreased in asthmatics belonging to purine, polyamine and fatty acid metabolism. Interestingly, a panel of carnitines were able to distinguish between sub-population of severe asthmatics. Lastly, investigating the effect of prebiotic supplementation to individuals with exercise-induced asthma, did not generate any statistically significant effect on SCFAs concentrations nor lung function, possibly due to the low levels of prebiotic supplementation. Open Access